FDA Adds Diabetes Warning to Statin Label

WASHINGTON -- The FDA said today that all statins must carry warnings about increased risks of elevated blood sugar and possible transient memory and cognition problems, but at the same time the agency removed a standing recommendation for routine liver function tests for patients taking the cholesterol-lowering drugs.

Despite the additional warnings, the FDA said it "continues to believe that the cardiovascular benefits of statins outweigh these small increased risks."

Rather than regular monitoring of liver function, the agency said that clinicians should now simply order a liver function test before starting a patient on a statin. Although the drugs do carry a risk of liver damage, the agency has judged the risk to be "rare and unpredictable in individual patients."

The diabetes warning has been rumored as a possibility since the findings from the JUPITER trial of rosuvastatin revealed an unexpected 27% increase in new onset diabetes among patients randomized to the statin.

That finding was especially perplexing because JUPITER was a study of statins in patients who had no history of cardiovascular disease, the so-called healthy patient trial. Moreover, based on the JUPITER results, the FDA approved rosuvastatin for primary prevention.

The FDA said hyperglycemia was also observed among patients treated with 40-mg atorvastatin in a substudy of PROVE-IT TIMI 22, and a meta-analysis of data from 13 statin trials "reported that statin therapy was associated with a 9% increased risk for incident diabetes."

The cognitive data are a bit sketchier and rely mainly on post-marketing adverse event reporting. The FDA said those reports "generally described individuals over the age of 50 years who experienced notable, but ill-defined memory loss or impairment that was reversible upon discontinuation of statin therapy."

In addition to those broad label changes, the FDA added a number of restrictions to the lovastatin (Mevacor) label, including a list of 10 drugs or drug classes that are contraindicated with lovastatin.

Drugs contraindicated with lovastatin include:

Itraconazole

Ketoconazole

Posaconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors

Boceprevir

Telaprevir

Nefazodone

Additionally, the new lovastatin label states that cyclosporine and gemfibrozil should be "avoided" when taking lovastatin, and lovastatin dosing should be limited to 20 mg for patients taking danazol, diltiazem, or verapamil. Finally, patients taking amiodarone should limit lovastatin to 40 mg daily.

In general, cardiologists contacted by ABC News/MedPage Today, applauded the FDA action -- particularly the decision to remove the requirement for liver function testing. Harlan Krumholz, MD, of Yale University, said, "Good news on liver testing -- provides no benefit and a lot of Americans are being monitored unnecessarily."

But Krumholz and others worried about patients being scared off statins by the diabetes and memory warnings.

"All drugs have side effects and rarely some patients will have an odd reaction to statins -- cognitive effects are among those, which are usually mild and resolve with stopping the medication. The blood sugar and diabetes issue has emerged over the last couple of years -- this appears to be a side effect," Krumholz wrote in an email.

Scott Grundy, MD, of the University of Texas Southwestern Medical Center in Dallas, was dubious about the level of evidence linking diabetes and cognition problems with statins. "I do not believe there is enough hard evidence to justify information and warnings about memory loss and confusion or increase in blood sugar."

And Grundy, too, worried about the impact on patients, writing, "I also think that these warnings will cause some people who need statins to stop taking them. That would be unfortunate."

The Cleveland Clinic's Steven Nissen, MD, often a critic of the FDA, told ABC News/MedPage Today, "these are reasonable and prudent recommendations. I am pleased that FDA did not overstate the diabetes and cognitive function risks. Both problems are uncommon and don't diminish the importance of statins in cardiovascular protection. For the vast majority of patients, the benefits far outweigh the risks."

Moreover, Nissen said, the FDA's decision on liver monitoring could boost statin use because it "will help to allay public apprehension about the liver safety of statins."

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